Background

Tumors are highly plastic metabolic entities composed of cancer and host cells that can adopt different metabolic phenotypes. For energy production, cancer cells may use 4 main fuels that are shuttled in 5 different metabolic pathways. Glucose fuels glycolysis that can be coupled to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in oxidative cancer cells or to lactic fermentation in proliferating and in hypoxic cancer cells. Lipids fuel lipolysis, glutamine fuels glutaminolysis, and lactate fuels the oxidative pathway of lactate, all of which are coupled to the TCA cycle and OXPHOS for energy production. This review focuses on the latter metabolic pathway.

Scope of review

Lactate, which is prominently produced by glycolytic cells in tumors, was only recently recognized as a major fuel for oxidative cancer cells and as a signaling agent. Its exchanges across membranes are gated by monocarboxylate transporters MCT1-4. This review summarizes the current knowledge about MCT structure, regulation and functions in cancer, with a specific focus on lactate metabolism, lactate-induced angiogenesis and MCT-dependent cancer metastasis. It also describes lactate signaling via cell surface lactate receptor GPR81.

Major conclusions

Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumor aggressiveness. Analyses of MCT-deficient (MCT^+/- and MCT^−/-) animals and (MCT-mutated) humans indicate that they are druggable, with MCT1 inhibitors being in advanced development phase and MCT4 inhibitors still in the discovery phase. Imaging lactate fluxes non-invasively using a lactate tracer for positron emission tomography would further help to identify responders to the treatments.

中文翻译：

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癌症中的单羧酸盐转运蛋白。

背景

肿瘤是高度可塑性的代谢实体，由癌症和可以采用不同代谢表型的宿主细胞组成。为了产生能量，癌细胞可以使用4种主要燃料，这些燃料以5种不同的代谢途径穿梭。葡萄糖可促进糖酵解，糖酵解可与氧化癌细胞中的三羧酸（TCA）循环和氧化磷酸化（OXPHOS）偶联，或与增殖和缺氧癌细胞中的乳酸发酵偶联。脂质促进脂解作用，谷氨酰胺促进谷氨酰胺分解，乳酸盐促进乳酸的氧化途径，所有这些都与TCA循环和OXPHOS耦合以产生能量。这篇综述着重于后者的代谢途径。

审查范围

乳酸由肿瘤中的糖酵解细胞显着产生，直到最近才被认为是氧化性癌细胞的主要燃料和信号传导剂。其跨膜的交换被单羧酸盐转运蛋白MCT1-4控制。这篇综述总结了有关MCT在癌症中的结构，调节和功能的当前知识，特别关注乳酸代谢，乳酸诱导的血管生成和MCT依赖性癌症转移。它还描述了通过细胞表面乳酸受体GPR81发出的乳酸信号。

主要结论

乳酸和MCT，尤其是MCT1和MCT4，是导致肿瘤侵袭性的重要因素。对MCT缺陷（MCT ^+/-和MCT ^-/-）动物和（MCT突变的）人类的分析表明，它们是可药物治疗的，其中MCT1抑制剂处于晚期发育阶段，而MCT4抑制剂仍处于发现阶段。使用乳酸示踪剂对正电子发射断层摄影术无创地对乳酸通量进行成像，将进一步帮助识别对治疗的反应者。